This is a competing renewal application for a P60 Center that was formed in 1987 with the theme of, improving treatment of addiction. At that point the critical mass of investigators with R01s from NIDA, NIAAA and even NIMH had become so large that a center structure with a large core to provide the infrastructure needed to coordinate a large number of clinical research projects was needed. After one term it was changed from a P50 mechanism to a P60 mechanism at the suggestion of then NIDA Director, Alan Leshner, because of the diversity of projects, education programs and dissemination programs conducted in the Center. It was felt by Dr. Leshner that the large size and diverse nature of activities of this Center required the flexibility of a P60 comprehensive research center. Thus, a major portion of the productivity of this Center is in its multiple educational programs for medical students, residents, undergraduates, postdoctoral fellows, minorities, community clinicians, probation officers, judges and legislators. As expected of a P60, we have always had a basic research component with an eye toward translation of findings from the lab to the clinic through clinical trials and the translation of technology from clinical trials to the community practitioner. Recent activities are described in the Progress Report. Our ultimate goal is to have an impact on clinical practice in the management of addictive disorders. Thus the over-arching theme of this Center has always been research that results in improvement of treatment of substance abuse. Admittedly, this is not a highly specific theme demanded of a P50 focused center, but rather an integrative theme in keeping with a P60 comprehensive center. Each of the four previous reviews since 1987 have commented on the broadness of this theme, but all concluded that it was appropriate for a P60 center of this kind. In this competing renewal application we present the accomplishments of the past five years, detail the operations of the Cores and propose four new projects: Proj. 1 is a basic project addressing opiate addiction by a study of Mu Opiate Receptor Interacting Proteins using well characterized samples obtained from patients in our clinical trials and NIH sources;.Proj. 2 addresses the growing problem of prescription opioid abuse by conducting a longitudinal study of primary care patients beginning treatment with opioids for chronic pain;Proj. 3 &4 address cocaine addiction and the spread of HIV. Proj. 3 proposes the study of an adaptive treatment for cocaine dependence;and Proj. 4 is a clinical trial of modafinil in women involved in trading sex for cocaine. Two proposed pilot projects focus on brain imaging of craving in marijuana and nicotine dependent patients using strategies developed in our prior studies of cocaine and opiate addiction.